The basic aim of the project is to investigate the biochemistry of the ovarian steroidal hormones (particularly progesterone) and their metabolites in regulating the hypothalmic-hypophyseal-ovarian axis. Specifically we hope to elucidate some of the biochemical regulatory mechanisms involved in these steroid feedbacks, at neural and pituitary levels, and the role of their metabolites in regulating gonadotropin secretion. The information gained is expected to give new insights into the steroidal regulatory mechanism(s) affecting the hypothalamic-ovarian axis, which might ultimately reveal new avenues for the control of fertility. Toward these ends we propose to explore during the next five year proposal the following: 1. The role of hypothalamic and pituitary metabolism of progesterone and to a lesser degree 20 alpha-dihydroprogesterone. The properties of these metabolizing enzymes and the factors affecting these transformations. 2. Identification of the specific site(s) of localization of progesterone and/or its metabolites and the factors which influence these interactions at tissue, cell and subcellular levels. 3. Attempts to integrate the interactions of estradiol and progesterone feedbacks primarily at neural and pituitary levels. 4. Examination of the biological effects and relevancy to progesterone of its 5 alpha-reduced metabolites particularly 5 alpha-dihydroprogesterone on gonadotropin release. 5. To elucidate the hypothalamic subcellular components involved in the storage and release of the gonadotropin releasing factor(s) and to a lesser degree biosynthesis; and their order of interaction and/or response to steroid feedbacks. The proposed experiments will utilize both in vivo and in vitro studies, steroid, protein and enzymic biochemical methods as well as cytological and physiological methods.